Obesity accounts for substantial cardiovascular disease (CVD) morbidity and mortality. A fundamental mediator of CVD risk in obesity is the development of insulin resistance and metabolic risk factors (glucose ntolerance, dyslipidemia, and hypertension). However, metabolic risk in obesity is heterogeneous. Activation of the RAAS is a key feature of obesity that may be reversed by weight loss. An activated RAAS triggers the release of NP, which are important counter-regulatory hormones. Unexpectedly, NP levels are depressed ather than elevated in obese individuals, suggesting that obesity is associated with a "natriuretic handicap," The RAAS and NP pathways exert important and opposing influences on glucose metabolism and adipocyte function. Further, pharmacological RAAS blockade is associated with a reduced incidence of diabetes. We hypothesize that the imbalance of renin-angiotensin-aldosterone system (RAAS) activation and natriuretic peptide (NP) downregulation in obese individuals contributes to heterogeneity in metabolic risk. We propose to test our hypothesis by obtaining serial measures of RAAS (plasma renin, angiotensin converting enzyme, aldosterone) and NP (N-terminal pro-B-type natriuretic peptide, N-terminal pro-atrial natriuretic peptide, cGMP) biomarkers, and relating them to longitudinal tracking of metabolic risk factors in a large, community- based cohort (Framingham Heart Study [FHS] 3rd generation and minority Omni 2nd generation participants). Our specific aims are (1) to examine the associations of obesity and longitudinal weight change (over 4 years) with circulating RAAS/NP biomarkers; (2) to relate RAAS/NP biomarkers to the risk of developing metabolic traits; and (3) to define the relations of common genetic variation in RAAS/NP genes with biomarker levels and metabolic traits, as a test of the etiologic importance of these pathways (Mendelian randomization). The FHS 3rd generation and Omni 2nd generation cohorts provide a large (n=4000), single- site, community-based sample of young adults with low CVD prevalence, but a high prevalence of obesity and metabolic risk factors. The scientific yield of the project will be enhanced by existing databases of metabolic and inflammatory markers funded via other mechanisms, extensive genetic resources, and a large replication cohort. Obese individuals have evidence of altered activity in 2 hormonal pathways (renin-angiotensin-aldosterone system, natriuretic peptide system), which may contribute to their susceptibility to developing conditions such as elevated blood sugar, high cholesterol, and hypertension. Assessment ofbiochemial markers of these pathways may identify obese individuals at higher risk of developing cardiovascular risk factors and may suggest novel therapeutic targets. [unreadable] [unreadable] [unreadable]